The National Institute on Drug Abuse (NMA) recently launched an Institute-wide initiative to expand scientific reseal on the behavioral neurobiology of methamphetamine with the hopes of applying the results of this march to the prevention and treatment of methamphetamine abuse. This "Methamphetamine Initiative" is aimed at increasing scientific knowledge regarding methamphetamine and providing the public and health care practitioners with the latest available information about the drug's use, consequences, prevention, and treatment. This initiative was issued in response to the concern that the abuse of methamphetamine has become an extremely serious and growing problem. Although the drug was first used primarily in selected urban areas in the Southwestern part of the United States, high levels of methamphetamine abuse are now being observed in many areas of the Midwest, in both urban and rural settings, and by very diverse segments of the population. This is a revised application developed in response to this "Methamphetamine Initiative" and describes experiments designed to determine the potential role for stress and the subsequent activation of the hypothalamo-pituitary-adrenal (EPA) axis in the behavioral neurobiology of methamphetamine reinforcement. The primary hypothesis for this application is that the EPA axis influences the reinforcing efficacy of methamphetamine in a manner similar to tee. The influence of stress in methamphetamine reinforcement will be investigated during all three aspects of methamphetamine self-eon: namely the acquisition, maintenance and reinstatement of methamphetamine-seeing behavior. In this application, we highlight research we have conducted during the last 10 years or so demonstrating an important role for stress, CRF and corticosterone in cocaine self-administration using methodology we have developed and/or refined to investigate these Factors. This application describes experiments designed to investigate the influence of these factors in methamphetamine reinforcement using very similar procedures. Together, these experiments will increase knowledge of how stress and the subsequent activation of the EPA axis influence methamphetamine reinforcement and may also suggest novel pharmacotherapies for the treatment of methamphetamine abuse and withdrawal in humans.